Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)

被引：145

作者：

Cao, Jia ^{[1
,2
,3
,4
]}

Meng, Shumei ^{[1
,2
,3
,4
]}

Chang, Evan ^{[1
,2
,3
,4
]}

Beckwith-Fickas, Katherine ^{[5
,6
,7
,8
]}

Xiong, Lishou ^{[1
,2
,3
,4
]}

Cole, Robert N. ^{[9
,10
,11
,12
]}

Radovick, Sally ^{[5
,6
,7
,8
]}

Wondisford, Fredric E. ^{[1
,2
,3
,4
]}

He, Ling ^{[1
,2
,3
,4
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Metab, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Dept Physiol, Div Metab, Baltimore, MD 21287 USA

[3] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Div Metab, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Dept Med, Div Metab, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Endocrinol, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Sch Med, Dept Physiol, Div Endocrinol, Baltimore, MD 21287 USA

[7] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Div Endocrinol, Baltimore, MD 21287 USA

[8] Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol, Baltimore, MD 21287 USA

[9] Johns Hopkins Univ, Sch Med, Dept Pediat, Mass Spectrometry & Prote Facil, Baltimore, MD 21287 USA

[10] Johns Hopkins Univ, Sch Med, Dept Physiol, Mass Spectrometry & Prote Facil, Baltimore, MD 21287 USA

[11] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Mass Spectrometry & Prote Facil, Baltimore, MD 21287 USA

[12] Johns Hopkins Univ, Sch Med, Dept Med, Mass Spectrometry & Prote Facil, Baltimore, MD 21287 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 30期

基金：

美国国家卫生研究院;

关键词：

HEPATIC GLUCONEOGENESIS; RESPIRATORY-CHAIN; CANCER; PHOSPHORYLATION; RISK; MICE; PHARMACOKINETICS; PHARMACODYNAMICS; INHIBITION; MECHANISM;

D O I：

10.1074/jbc.M114.567271

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60-80 mu M). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the alpha subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPK alpha phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.

引用

页码：20435 / 20446

页数：12

共 39 条

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